Vasopressin, a neuroyhpophyseal neuropeptide produced in the hypothalamus, is involved in water metabolism homeostasis, renal function, mediation of cardiovascular function, non-opioid mediation of tolerance for pain, and regulation of temperature in mammals. In addition to being released into the circulation via the posterior pituitary, vasopressin acts as a neurotransmitter in the brain. Three vasopressin receptor subtypes, designated V1a, V1b, and V2 have been identified. The human V1a receptor has been cloned (Thibonnier et al., The Journal of Biological Chemistry, 269(5), 3304-3310 (1994)), and has been shown by radioligand binding techniques to be present in vascular smooth muscle cells, hepatocytes, blood platelets, lymphocytes and monocytes, type II pneumocytes, adrenal cortex, brain, reproductive organs, retinal epithelium, renal mesangial cells and the A10, A7r5, 3T3 and WRK-1 cell lines (Thibonnier, Neuroendocrinology of the Concepts in Neurosurgery Series 5, (Selman, W., ed), 19-30, Williams and Wilkins, Baltimore, (1993)).
Structural modification of vasopressin has provided a number of vasopressin agonists (Sawyer, Pharmacol. Reviews, 13, 255 (1961)). In the past decade, several potent and selective vasopressin peptide antagonists have been designed (Lazslo, et al., Pharmacological Reviews, 43, 73-108 (1991); Mah and Hofbauer, Drugs of the Future, 12, 1055-1070 (19871; Manning and Sawyer, Trends in Neuroscience, 7, 8-9 (1984)). Their lack of oral bioavailability and short half-life, however, have severely limited their therapeutic potential. While novel structural classes of non-peptidyl vasopressin V1a antagonists have been discovered (Yamamura, et al., Science, 275, 572-574 (1991); Serradiel-Le Gal, et al., Journal of Clinical Investigation, 92, 224-231 (1993); Serradiel-Le Gal, et al., Biochemical Pharmacology, 47(4), 633-641 (1994)), a clinically useful agent is yet to be identified.
The general structural class of substituted 2-(azetidin-2-on-1-yl)acetic acid esters and amides are well known in the art as synthetic intermediates for the preparation of xcex2-lactam antibiotics (U.S. Pat. No. 4,751,299). While certain compounds within this structural class have been reported as possessing antibiotic activity, their activity at the vasopressin V1a receptor has heretofore not been appreciated.
This invention provides a method for the antagonism of the vasopressin V1a receptor comprising administering to a mammal in need of such antagonism a pharmaceutically effective amount of a 2-(azetidin-2-on-1-yl)acetic acid derivative of Formula I 
where
R1 is hydrogen, C1-C5 alkyl, xe2x80x94C(O)NR5Xxe2x80x2, (C1-C4 alkylene)C(O)NR5Xxe2x80x2, hydroxy substituted C1-C5 alkyl, C1-C5 acyl optionally substituted as the ethylene glycol ketal, C3-C6 cycloalkylcarbonyl, benzoyl, phenyl, phenyl(C1-C4 alkylene), phenoxyacetyl, phenylacetyl where the phenyl is optionally substituted with halo, C1-C4 alkyl, C1-C4 alkoxy, or trifluoromethyl, or xcex1-hydroxy-xcex1-benzoylbenzyl;
R2 is hydrogen, or hydroxy substituted C1-C5 alkyl;
R3 is phthalimido, azido, phenoxyacetamido, 4,5-diphenyloxazol-2-on-3-yl, or a structure selected from the group consisting of 
R4 is:
phenethyl, or 2-arylethen-1-yl where aryl is selected from the group consisting of furyl, pyrrolyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrimidinyl, thiadiazolyl, oxadiazolyl, quinolyl, isoquinolyl, naphthyl, and phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, nitro, halo, carboxy, and amido;
Q is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR5xe2x80x94;
R5 is hydrogen, hydroxy, C1-C4 alkoxycarbonyl, benzyl, or C1-C4 alkyl;
R6 is C1-C8 alkyl, C3-C8 cycloalkyl, phenyl, or phenyl(C1-C4 alkylene) optionally substituted on the alkylene chain with C1-C4 alkoxycarbonyl;
X and Xxe2x80x2 are independently hydrogen, C1-C6 alkyl, 2-(trimethylsilyl)ethyl, C1-C4 alkyl xcfx89-substituted with C1-C4 alkoxy, Y, (optionally substituted C1-C4 alkylene)-Y, or (optionally substituted C2-C4 alkylene)-NR7R8;
Y is phenyl, optionally substituted phenyl, diphenylmethyl, C3-C6 cycloalkyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl, pyrrolyl, 1-(C1-C4 alkyl)pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, furyl, benzodioxanyl, tetrahydrofuryl, pyrrolidinyl, 1-(C1-C4 alkyl)pyrrolidinyl, 1-benzylpyrrolidinyl, piperidinyl, 1-benzylpiperidin-4-yl, or quinuclidinyl;
R7 is hydrogen, or C1-C4 alkyl;
R8 is C1-C4 alkyl, phenyl, or pyridinyl optionally substituted with nitro;
R7 and R8 taken together with the nitrogen atom to which they are attached form morpholinyl, optionally substituted piperazinyl, or pyrrolidinyl;
R5 and Xxe2x80x2 taken together with the nitrogen to which they are attached form:
2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl;
piperidinyl optionally substituted at the 4-position with hydroxy, pyrrolidin-1-yl, piperidin-1-yl, benzyl, or piperidin-1-yl(C1-C4 alkylene);
piperidinyl mono- or disubstituted with methyl;
piperazinyl optionally substituted at the 4-position with C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, phenyl(C1-C4 alkylene), xcex1-methylbenzyl, Nxe2x80x94(C1-C4 alkyl)acetamid-2-yl, or C1-C4 alkoxycarbonyl;
1,2,3,4-tetrahydroisoquinolin-2-yl; or
homopiperazinyl substituted in the 4-position with C1-C4 alkyl;
R2, Q, and X taken together with the bridging carbon atoms to which they are attached form the lactone 
R10 is C1-C6 alkyl, C3-C6 cycloalkyl, phenyl(C1-C4 alkylene) where the phenyl is optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or halo, naphthyl, thienyl, furyl, benzothienyl, benzofuryl, or phenyl optionally monosubstituted with C1-C4 alkyl, C1-C4 alkoxy or halo;
R11 is C1-C4 alkyl, C3-C7 cycloalkyl, phenyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano; carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and nitro, naphthyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, and nitro, or C1-C4 alkoxycarbonyl;
R12 is:
C1-C4 alkyl optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl and C1-C4 thioalkyl;
phenyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and nitro;
naphthyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, and nitro; or
C1-C4 alkoxycarbonyl;
R13 is:
C1-C4 alkoxycarbonyl;
benzyloxycarbonyl where the phenyl group is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, amino, carbamoyl, hydroxy, mono(C1-C4 alkyl)amino, and di(C1-C4 alkyl)amino;
benzoyl where the phenyl group is optionally substituted with one or two substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and nitro; and
R14 and R15 are:
C1-C5 alkanoyloxy,
benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, amino and C1-C4 alkoxycarbonyl;
benzyloxy;
diphenylmethoxy; or
triphenylmethoxy; or
one of R14 and R15 is hydrogen and the other is:
C1-C5 alkanoyloxy;
benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, amino and C1-C4 alkoxycarbonyl;
benzyloxy;
diphenylmethoxy; or
triphenylmethoxy;
providing that R2 may be other than hydrogen only when R1 is hydroxy substituted C1-C5 alkyl; and hydrates, solvates and pharmaceutically acceptable acid addition salts thereof.
Certain compounds of Formula I are novel. A further embodiment of this invention are novel substituted 2-(azetidinon-1-yl)acetic acid derivatives of Formula II 
where
A is xe2x80x94Oxe2x80x94R9; xe2x80x94Sxe2x80x94Xxe2x80x3; or xe2x80x94NR5Xxe2x80x3;
R1; R2; R4; R5; R7; R8; R10; R11; R12; R13; R14; R15; and Y are as previously defined;
R3xe2x80x2 is a structure selected from the group consisting of: 
Xxe2x80x3 is C1-C4 alkylene xcfx89-substituted with C1-C4 alkoxy, Y, (optionally substituted C1-C4 alkylene)-Y, or (optionally substituted C2-C4 alkylene)-NR7R8;
R5 and Xxe2x80x3 taken together with the nitrogen to which they are attached form:
2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl;
piperidinyl optionally substituted at the 4-position with hydroxy, pyrrolidin-1-yl, piperidin-1-yl, benzyl, or piperidin-1-yl(C1-C4 alkylene);
piperidinyl mono- or disubstituted with methyl;
piperazinyl optionally substituted at the 4-position with C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, phenyl(C1-C4 alkylene), xcex1-methylbenzyl, Nxe2x80x94(C1-C4 alkyl)acetamid-2-yl, or C1-C4 alkoxycarbonyl;
1,2,3,4-tetrahydroisoquinolin-2-yl; or
homopiperazinyl substituted in the 4-position with C1-C4 alkyl;
R9 is C1-C6 alkyl, (C2-C4 alkylene)trimethylsilyl, or benzyl where the phenyl ring of the benzyl moiety may be optionally substituted with 1 to 3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy, nitro, amino, cyano, hydroxy, or carboxamido;
providing that:
a) R2 may be other than hydrogen only when R1 is hydroxy substituted C1-C5 alkyl; and
b) when A is xe2x80x94OR9, R1 must be selected from the group consisting of xe2x80x94C(O)NR5Xxe2x80x2, (C1-C4 alkylene)C(O)NR5Xxe2x80x2, and 2,2-dimethylpropanoyl;
and solvates and pharmaceutically acceptable acid addition salts thereof.
This invention also provides a pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of Formula II.
The general chemical terms used in the formulae above have their usual meanings. For example, the term xe2x80x9calkylxe2x80x9d includes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like.
The term xe2x80x9calkoxyxe2x80x9d includes such groups as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.
The term xe2x80x9cacylxe2x80x9d includes such groups as formyl, acetyl, propanoyl, butanoyl, pentanoyl and the like.
The term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo, and iodo.
The term xe2x80x9ccycloalkylxe2x80x9d means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term xe2x80x9calkanoyloxyxe2x80x9d refers to formyloxy, acetoxy, n-propionoxy, n-butyroxy, pivaloyloxy, and like lower alkanoyloxy groups.
The term xe2x80x9chydroxy substituted alkylxe2x80x9d is taken to mean a linear or branched alkyl radical which bears a hydroxy substituent on the carbon at the point of attachment of the radical to the rest of the molecule. Such groups include hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxy-2,2-dimethylpropyl, and the like.
The term xe2x80x9cphenyl(C1-C4 alkylene)xe2x80x9d is taken to mean a linear or branched alkyl chain of from one to four carbons bearing as a substituent a phenyl ring. Examples of such groups include benzyl, phenethyl, phenpropyl, xcex1-methylbenzyl and the like.
The term xe2x80x9coptionally substituted phenylxe2x80x9d is taken to mean a phenyl radical optionally substituted with one or two substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, nitro, trifluoromethyl, sulfonamido, and indol-2-yl.
The terms xe2x80x9c(optionally substituted C1-C4 alkylene)xe2x80x9d and xe2x80x9c(optionally substituted C2-C4 alkylene)xe2x80x9d are taken to mean an alkylene chain which is optionally substituted with up to two methyl groups or a C1-C4 alkoxycarbonyl group.
The term xe2x80x9cprotected aminoxe2x80x9d refers to amine protecting groups used to protect the nitrogen of the xcex2-lactam ring during preparation or subsequent reactions. Examples of such groups are benzyl, 4-methoxybenzyl, 4-methoxyphenyl, or trialkylsilyl, for example trimethylsilyl.
The term xe2x80x9cprotected carboxyxe2x80x9d refer to the carboxy group protected or blocked by a conventional protecting group commonly used for the temporary blocking of the acidic carboxy. Examples of such groups include lower alkyl, for example tert-butyl, halo-substituted lower alkyl, for example 2-iodoethyl and 2,2,2-trichloroethyl, benzyl and substituted benzyl, for example 4-methoxybenzyl and 4-nitrobenzyl, diphenylmethyl, alkenyl, for example allyl, trialkylsilyl, for example trimethylsilyl and tert-butyldiethylsilyl and like carboxy-protecting groups.
The term xe2x80x9cantagonistxe2x80x9d, as it is used in the description of this invention, is taken to mean a full or partial antagonist. A compound which is a partial antagonist at the vasopressin V1a receptor must exhibit sufficient antagonist activity to inhibit the effects of vasopressin or a vasopressin agonist at an acceptable dose. While a partial antagonist of any intrinsic activity may be useful, partial antagonists of at least about 50% antagonist effect are preferred and partial antagonists of at least about 80% antagonist effect are more preferred. Full antagonists of the vasopressin V1a receptor are most preferred.
While all of the compounds of Formula I and Formula II are useful, certain classes are preferred. The following paragraphs describe such preferred classes.
a) R1 is selected from the group consisting of C1-C4 alkyl, xe2x80x94C(O)NR5Xxe2x80x2, xe2x80x94(C1-C4 alkylene)C(O)NR5Xxe2x80x2, hydroxy substituted C1-C5 alkyl, C1-C5 acyl optionally substituted as the ethylene glycol ketal, and xcex1-hydroxy-xcex1-benzoylbenzyl;
ab) R1 is C1-C4 alkyl;
ac) R1 is isopropyl;
ad) R1 is isobutyl;
ae) R1 is xe2x80x94C(O)NR5Xxe2x80x2;
af) R1 is xe2x80x94(C1-C4 alkylene)C(O)NR5Xxe2x80x2;
ag) R1 is hydroxy substituted C1-C5 alkyl;
ag) R1 is 1-hydroxy-2,2-dimethylpropyl;
ai) R1 is C1-C5 acyl optionally substituted as the ethylene glycol ketal;
aj) R1 is 2,2-dimethylpropanoyl;
ak) R1 is acetyl ethylene glycol ketal;
al) R1 is propanoyl ethylene glycol ketal;
am) R1 is xcex1-hydroxy-xcex1-benzoylbenzyl;
an) R2 is hydrogen;
ao) R2 is 1-hydroxy-2,2-dimiethylpropyl;
ap) R3 is 4-substituted oxazolidin-2-on-3-yl;
aq) R3 is 2,5-disubstituted oxazolidin-4-on-3-yl;
ar) R3 is 1,2,5-trisubstituted imidazolidin-4-on-3-yl;
as) R3 is 3,4-disubstituted succinimido;
at) R3 is 3-substituted succinimido;
au) R4 is 2-arylethen-1-yl;
av) R4 is 2-phenylethen-1-yl;
aw) Q is xe2x80x94Oxe2x80x94;
ax) Q is xe2x80x94NR5xe2x80x94;
ay) R5 is hydrogen;
az) R5 is benzyl;
ba) X or Xxe2x80x2 is (optionally substituted C1-C4 alkylene)-Y;
bb) X or Xxe2x80x2 is xe2x80x94CH2xe2x80x94Y;
bc) Y is phenyl;
bd) Y is substituted phenyl;
be) Y is phenyl monosubstituted in the 3-position;
bf) Y is quinuclidinyl;
bg) Y is tert-butyl;
bh) X or Xxe2x80x2 is (optionally substituted C2-C4 alkylene)-NR7R8;
bi) R7 is C1-C4 alkyl;
bj) R8 is C1-C4 alkyl;
bk) R7 and R8 are both methyl;
bl) R7 and R8 are both ethyl;
bm) R7 is hydrogen and R8 is 5-nitropyridin-2-yl;
bn) R5 and Xxe2x80x2 taken together with the nitrogen to which they are attached form a moiety selected from the group consisting of piperidinyl substituted in the 4-position with hydroxy or piperidin-1-yl(C1-C4 alkylene), piperidinyl mono- or disubstituted with methyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, piperazinyl substituted in the 4-position with methyl, xcex1-methylbenzyl, or phenethyl, and homopiperazinyl substituted in the 4-position with methyl;
bo) R5 and Xxe2x80x2 taken together with the nitrogen to which they are attached form piperidinyl substituted in the 4-position with hydroxy or piperidin-1-yl(C1-C4 alkylene);
bp) R5 and Xxe2x80x2 taken together with the nitrogen to which they are attached form piperidinyl mono- or disubstituted with methyl;
bq) R5 and Xxe2x80x2 taken together with the nitrogen to which they are attached form 1,2,3,4-tetrahydroisoquinolin-2-yl;
br) R5 and Xxe2x80x2 taken together with the nitrogen to which they are attached form piperazinyl substituted in the 4-position with methyl, (xcex1-methylbenzyl, or phenethyl;
bs) R5 and Xxe2x80x2 taken together with the nitrogen to which they are attached form homopiperazinyl substituted in the 4-position with methyl.
It will be understood that the above classes may be combined to form additional preferred classes.
Especially preferred compounds of Formulae I and II are those described by Formula III 
where
aryl is phenyl, 2-furyl, or 3-furyl;
R1xe2x80x2 is hydrogen;
R2xe2x80x2xe2x80x3 is selected from the group consisting of isopropyl, isobutyl, 1-hydroxy-2,2-dimethylpropyl, acetyl ethylene glycol ketal, propanoyl ethylene glycol ketal, 2,2-dimethylpropanoyl, xe2x80x94C(O)NR5xe2x80x2Xxe2x80x2xe2x80x3, and xe2x80x94(C1-C4 alkylene)C(O)xe2x80x94NR5xe2x80x2Xxe2x80x2xe2x80x3;
A is xe2x80x94Oxe2x80x94R9xe2x80x2; or xe2x80x94NR5xe2x80x2Xxe2x80x2xe2x80x3;
R5xe2x80x2 is hydrogen;
R9xe2x80x2 is benzyl;
Xxe2x80x2xe2x80x3 is xe2x80x94CH2xe2x80x94Yxe2x80x2;
Yxe2x80x2 is substituted phenyl;
R5xe2x80x2 and Xxe2x80x2xe2x80x3 taken together with the nitrogen to which they are attached form a moiety selected from the group consisting of:
1,2,3,4-tetrahydroisoquinolin-2-yl;
piperidinyl substituted in the 4-position with hydroxy or piperidin-1-yl(C1-C4 alkylene);
piperidinyl mono- or disubstituted with methyl; and
piperazinyl substituted in the 4-position with xcex1-methylbenzyl or phenethyl.
The compounds of the present invention are comprised of an azetidinone nucleus, said nucleus bearing asymmetric carbons at the 3- and 4-positions as illustrated in the following figure: 
The compounds of the invention may, therefore, exist as single diastereomers, mixtures of diastereomers, or as a racemic mixture, all of which are useful and part of the invention. It is preferred that the azetidinone nucleus of the compounds of the invention exist in a single diastereomeric form. It is most preferred that the azetidinone nucleus exist as the 3(S),4(R)-diastereomer.
The skilled artisan will appreciate that, in most cases, the carbon bearing R1 and R2 is asymmetric. Furthermore, when R3 is 4-substituted oxazolidin-2-on-3-yl, the 4-position of that ring is asymmetric. When R3 is 2,5-disubstituted oxazolidin-4-on-3-yl or 1,2,5-trisubstituted imidazolidin-4-on-3-yl, the 2- and 5-carbons of those rings are asymmetric and, finally, when R3 is succinimido and one of R14 and R15 is hydrogen, the carbon bearing the non-hydrogen substituent is also asymmetric. While compounds possessing all combinations of stereochemical purity are contemplated, it is preferred that each of these chiral centers be of a single absolute configuration.
The compounds of this invention are useful in methods for antagonism of the vasopressin V1a receptor for treating a variety of disorders which have been linked to this receptor in mammals. It is preferred that the mammal to be treated by the administration of compounds of this invention is human.
Since certain of the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluene-sulfonic acid, methanesulfonic acid, oxalic acid, p-bromo-phenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex2-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid, trifluoroacetic acid, maleic acid or fumaric acid.
The following group is illustrative of compounds contemplated within the scope of this invention:
methyl 2(R)-isopropyl-2-[3(S)-(4(S)-(benzofur-7-yl)oxazolidin-2-on-3-yl)-4(R)-(1-(fur-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
ethyl 2(R)-isobutyl-2-[3(S)-(4(R)-(benzofur-2-yl)-oxazolidin-2-on-3-yl)-4(R)-(1-(pyrrol-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
propyl 2(R)-[1-hydroxy-2,2-dimethylpropyl]-2-[3(S)-4(S)-(benzothien-5-yl)oxazolidin-2-on-3-yl)-4(R)-(1-(pyrrol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
isopropyl 2(R)-[(1,1-ethyleneketal)propionyl]-2-[3(S)-(4(S)-(benzothien-5-yl)oxazolidin-2-on-3-yl)-4(R)-(1-(pyridin-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
butyl 2(R)-[(1,1-ethyleneketal)acetyl]-2-[3(S)-(4(S)-(benzothien-3-yl)oxazolidin-2-on-3-yl)-4(R)-(1-(pyridin-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
isobutyl 2(R)-[2,2-dimethylpropionyl]-2-[3(S)-(4(S)(fur-3-yl)oxazolidin-2-on-3-yl)-4(R)-(1-(pyridin-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
sec-butyl 2(R)-[N-benzylcarboxamido]-2-[3(R)-(4(S)-(thien-2-yl)oxazolidin-2-on-3-yl)-4(S)-(1-(thiazol-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
tert-butyl 2(R)-[N-(3-trifluoromethyl)benzylcarboxamido]-2-[3(S)-(naphth-2-yl)-4(R)-(1-(thiazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
pentyl 2(R)-[N-(3-amino)benzylacetamido-2-yl]-2-[3(S)-(4(S)-(phenpropyl)oxazolidin-2-on-3-yl)-4(R)-(1-(thiazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
hexyl 2(R)-[N-(2-trifluoromethyl)benzylacetamido-2-yl)-2-[3(S)-(4(S)-(phenethyl)oxazolidin-2-on-3-yl)-4(R)-(1-(oxazol-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
benzyl 2(R)-[N-(2-carboxamido)benzylpropionamido-3-yl]-2-[3(S)-(4(S)-(3-isopropylbenzyl)oxazolidin-2-on-3-yl)-4(R)-(1-(oxazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2-chlorobenzyl 2(R)-[N-(4-trifluoromethyl)benzylpropionamido-3-yl]-2-[3(R)-(4(S)-(4-fluorobenzyl)oxazolidin-2-on-3-yl)-4(S)-(1-(oxazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-fluorobenzyl 2(R)-[N-(4-nitro)benzylbutanamido-4-yl]-2-[3(S)-(4(S)-(benzyl)oxazolidin-2-on-3-yl)-4(R)-(1-(isoxazol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-iodobenzyl 2(R)-[N-(3-fluoromethyl)benzylbutanamido-4-yl]-2-[3(S)-(4(S)-(4-methoxyphenyl)oxazolidin-2-on-3-yl)-4(R)-(1-(isoxazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3,4-dibromobenzyl 2(R)-[N-(2-methoxy)benzylpentanamido-5-yl]-2-[3(S)-(4(S)-(3-chlorophenyl)oxazolidin-2-on-3-yl)-4(R)-(1-(isoxazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2-methylbenzyl 2(R)-[N-(4-methyl)benzylpentanamido-5-yl]-2-[3(S)-(4(S)-(2-ethylphenyl)oxazolidin-2-on-3-yl)-4(R)-(1-(imidazol-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-ethylbenzyl 2(S)-isopropyl-2-[3(S)-(4(R)-phenyloxazolidin-2-on-3-yl)-4(R)-(1-(imidazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-isopropylbenzyl 2(S)-isobutyl-2-[3(S)-(4(S)-cyclopropyloxazolidin-2-on-3-yl)-4(R)-(1-(imidazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-bromo-4-tert-butylbenzyl 2(S)-[1-hydroxy-2,2-dimethylpropyl]-2-[3(S)-(4(S)-cyclobutyloxazolidin-2-on-3-yl)-4(R)-(1-(pyrazol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-methoxybenzyl 2(S)-[1,1-ethylene)ketalpropionyl]-2-[3(R)-(4(S)-cyclopentyloxazolidin-2-on-3-yl)-4(S)-(1-(pyrazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-ethoxybenzyl 2(S)-[1,1-ethyleneketal)acetyl-2-[3(S)-(4(S)-cyclohexyloxazolidin-2-on-3-yl)-4(R)-(1-(pyrazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2-isopropylbenzyl 2(S)-[2,2-dimethylpropionyl]-2-[3(S)-(4(S)-hexyloxazolidin-2-on-3-yl)-4(R)-(1-(pyrimidin-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-tert-butyl-4-chlorobenzyl 2(S)-[N-benzylcarboxamido]-2-[3(R)-(4(S)-methyloxazolidin-2-on-3-yl)-4(S)-(1-(pyrimidin-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-nitrobenzyl 2(S)-[N-(3-trifluoromethyl)benzylcarboxamido]-2-[3(S)-(4(S)-tert-butyloxazolidin-2-on-3-yl)-4(R)-(1-(pyrimidin-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-aminobenzyl 2(S)-[N-(3-methylamino)benzylacetamido-2-yl]-2-[3(S)-(4(S)-isobutyloxazolidin-2-on-3-yl)-4(R)-(1-(pyrimidin-6-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-methyl-3,5-dichlorobenzyl 2(S)-[N-(3-dimethylamino)benzylacetamido-2-yl]-2-[3(S)-(4(S)-butyloxazolidin-2-on-3-yl)-4(R)-(1-(thiadiazol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2-cyanobenzyl 2(S)-[N-(2-trifluoromethyl)benzylpropionamido-3-yl]-2-(3(S)-(4(S)-isopropyloxazolidin-2-on-3-yl)-4(R)-(1-(oxadiazol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-hydroxybenzyl 2(S)-[N-(3-carboxamido)benzylpropionamido-3-yl]-2-[3(S)-(4(S)-propyloxazolidin-2-on-3-yl)-4(R)-(1-(quinolin-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-carboxamidobenzyl 2(S)-[N-(4-trifluoromethyl)benzylbutanamido-4-yl]-2-[3(S)-(4(S)-ethyloxazolidin-2-on-3-yl)-4(R)-(1-(quinolin-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2,4,5-trichlorobenzyl 2(S)-(N-(2-nitro)benzylbutanamido-4-yl]-2-[3(S)-(4(S)-methyloxazolidin-2-on-3-yl)-4(R)-(1-(quinolin-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
N-[phenyl]-2(S)-[N-(2-fluoro-3-methyl)benzylbutanamido-4-yl]-2-[3(S)-(2-(6-nitronaphth-2-yl)-5-(methyl)-oxazolidin-4-on-3-yl)-4(R)-(1-(quinolin-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-trifluoromethylbenzyl]-2(S)-[N-(4-methoxy)benzylpentanamido-5-yl]-2-[3(S)-(2-(6-cyanonaphth-2-yl)-5-(hydroxymethyl)oxazolidin-4-on-3-yl)-4(R)-(1-(quinolin-6-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[cyclopropyl]-2(S)-[N-(4-isopropyl)benzylpentanamido-5-yl]-2-[3(S)-(2-(4-methylnaphth-2-yl)-5-ethyloxazolidin-4-on-3-yl)-4(R)-(1-(quinolin-7-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[cyclobutylethyl]-2(R,S)-isopropyl-2-[3(S)-2-(naphth-2-yl)-5-(2-(methoxycarbonyl)ethyl)oxazolidin-4-on-3-yl)-4(R)-(1-(quinolin-8-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[cyclopentyl]-2(R,S)-isobutyl-2-(3(S)-(5-methoxynaphth-1-yl)-5-(2-(benzyloxycarbonyl)ethyloxazolidin-4-on-3-yl)-4(R)-(1-(isoquinolin-1-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-(phenethyl]-2(R,S)-[1-hydroxy-2,2-dimethylpropyl]-2-[3(S)-(2-(3-chloro-1-naphthyl)-5-((phenoxycarbonyl)ethyl)-oxazolidin-4-on-3-yl)-4(R)-(1-(isoquinolin-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[phenpropyl]-2(R,S)-[(1,1-ethyleneketal)propioyl]-2-[3(S)-(2-(naphth-1-yl)-5-(propyl)oxazolidin-4-on-3-yl)-4(R)-(1-(isoquinolin-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-trifluoromethylbenzyl]-2(R,S)-[(1,1-ethyleneketal)acetyl]-2-[3(S)-(2-(3-nitrophenyl)-5-((3-thiobenzyl)propyl)oxazolidin-4-on-3-yl)-4(R)-(1-(isoquinolin-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[4-chlorobenzyl]-2(R,S)-[2,2-dimethylpropionyl)-2-[3(S)-(2-(3-nitrophenyl)-5-((3-thiobenzyl)propyl)oxazol-idin-4-on-3-yl)-4(R)-(1-(isoquinolin-6-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[2-bromobenzyl]-2(R,S)-[N-benzylcarboxamido]-2-[3(S)-(2-(4-methanesulfonylphenyl)-5-(isopropyl)oxazolidin-4-on-3-yl)-4(R)-(1-(isoquinolin-7-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-fluorobenzyl)-2(R,S)-[N-(3-trifluoromethyl)benzylcarboxamido]-2-[3(S)-(2-(3-aminophenyl)-5-(butyl)oxazolidin-4-on-3-yl)-4(R)-(1-(isoquinolin-8-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[2-methylbenzyl]-2(R,S)-[N-phenylcarboxamido]-2-[3(S)-(2-(2-cyanophenyl)-5-((3-thiomethyl)butyl)oxazolidin-4-on-3-yl)-4(R)-(1-(naphth-1-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-chloro-4-isopropylbenzyl]-2(R,S)-[N-(2-chlorophenyl)carboxamido]-2-[3(S)-(2-(4-hydroxyphenyl)-5-(isobutyl)oxazolidin-4-on-3-yl)-4(R)-(1-(naphth-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[2,4-dimethoxybenzyl]-2(R,S)-[N-(4-methylphenyl)carboxamido-2-[3(S)-(2-(2-fluoro-4-methoxyphenyl)-5-(phenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(2-fluorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-isopropoxybenzyl]-2(R,S)-[N-(3-isopropylphenyl)carboxamido]-2-[3(S)-(2-(3-ethoxyphenyl)-5-(2-methylphenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(3-chlorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[4-sulfonamidobenzyl]-2(R,S)-[N-(4-trifluoromethylphenyl)carboxamido]-2-[3(S)-(2-(2-methoxyphenyl)-5-(3-ethoxyphenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(4-bromophenyl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[quinuclidin-2-yl]-2(R,S)-[N-(4-methylphenyl)carboxamido]-2-[3(S)-(2-(3-isopropylphenyl)-5-(4-chlorophenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(3-iodophenyl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
1-{2(R,S)-(N-(3-trifluoramethylbenzyl)acetamido-2-yl]-2-[3(S)-(2-(2-chloro-4-bromophenyl)-5-(2-ethyl-3-bromophenyl)-oxazolidin-4-on-3-yl)-4(R)-(1-(2-methylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-1,2,3,4-tetrahydronaphthalene
1-{2(R,S)-[N-(benzyl)acetamido-2-yl]-2-[3(S)-(2-(2-chloro-4-bromophenyl)-5-(2-ethyl-3-bromophenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(3-isopropylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-hydroxypiperidine
1-{2(R,S)-[N-(4-chlorophenyl)acetamido-2-yl]-2-[3(S)-(2-(3-iodophenyl)-5-(3-hydroxyphenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(4-pentylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}4-(piperidin-1-yl)piperidine
1-{2(R,S)-[N-(2-cyanophenyl)acetamido-2-yl]-2-[3(R)-(2-(4-fluorophenyl)-5-(4-cyanophenyl)oxazolidin-4-on-3-yl)-4(S)-(1-(2-propoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-benzylpiperidine
1-{2(R,S)-[N-(phenylethyl)acetamido-2-yl]-2-[3(S)-(2-(phenyl)-5-(3-dimethylaminophenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(3-methoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-((piperidin-1-yl)methyl)piperidine
1-{2(R,S)-[N-(benzyl)propionamido-3-yl]-2-[3(S)-(2-(methoxycarbonyl)-5-(4-ethylaminophenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(4-isobutoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine
1-{2(R,S)-[N-(3-trifluoromethylbenzyl)propionamido-3-yl]-2-[3(R)-(2-(isobutoxycarbonyl)-5-(2-methanesulfonylaminophenyl)oxazolidin-4-on-3-yl)-4(S)-(1-(2-ethylthiophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(3-(piperidin-1-yl)propyl)piperidine
1-{2(R,S)-[N-(3-fluorophenyl)propionamido-3-yl]-2-[3(S)-(2-(cyclohexyl)-5-(3-nitrophenyl)oxazolidin-4-on-3-yl)-4(R)-(1-(3-hexylthiophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(4-(piperidin-1-yl)butyl)piperidine
1-{2(R,S)-[N-(3-aminophenyl)propionamido-3-yl]-2-[3(S)-(2-(cyclopentyl)-5-(methoxycarbonyl)oxazolidin-4-on-3-yl)-4(R)-(1-(4-methylthiophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-2,4-dimethylpiperidine
1-{2(R,S)-[N-(benzyl)propionamido-3-yl]-2-[3(S)-(2-(cyclopropyl)-5-(ethoxycarbonyl)oxazolidin-4-on-3-yl)-4(R)-(1-(2-nitrophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-3,5-dimethylpiperidine
1-{2(R,S)-[N-(3-methylbenzyl)propionamido-3-yl]-2-[3(S)-(2-(sec-butyl)-5-(tert-butoxycarbonyl)oxazolidin-4-on-3-yl)-4(R)-(1-(3-nitrophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-methylpiperidine
1-{2(R,S)-[N-(4-isopropoxybenzyl)propionamido-3-yl]-2-[3(S)-(2-(butyl)-5-(naphth-1-yl)oxazolidin-4-on-3-yl)-4(R)-(1-(4-nitrophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-isopropylpiperazine
1-{2(R,S)-[N-(3-iodobenzyl)propionamido-3-yl]-2-[3(S)-(2-(isopropyl)-5-(naphth-2-yl)oxazolidin-4-on-3-yl)-4(R)-(1-(2-carboxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-phenethylpiperazine
1-{2(R,S)-[N-(phenethyl)propionamido-3-yl]-2-[3(S)-(2-(propyl)-5-(3-chloronaphth-1-yl)oxazolidin-4-on-3-yl)-4(R)-(1-(3-carboxamidophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-cyclohexylpiperazine
1-{2(R,S)-[N-(benzyl)butanamido-4-yl]-2-[3(S)-(2-(ethyl)-5-(6-methoxynaphth-2-yl)oxazolidin-4-on-3-yl)-4(R)-(1-(-2,3-difluorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-cyclopropylpiperazine
1-{2(R,S)-[N-(3-trifluoromethylbenzyl)butanamido-4-yl]-2-[3(S)-(2-(methyl)-5-(5-aminonaphth-1-yl)oxazolidin-4-on-3-yl)-4(R)-(1-(3,5-dichlorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-benzylpiperazine
1-{2(R,S)-[N-(2-bromobenzyl)butanamido-4-yl]-2-[3(S)-(2-(isobutoxycarbonyl)-3-(methoxycarbonyl)-4-(3-dimethylaminophenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(3-chloro-4-bromophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-phenpropylpiperazine
1-{2(R,S)-[N-(phenyl)butanamido-4-yl]-2-[3(S)-(2-(cyclohexyl)-3-(ethoxycarbonyl)-4-(4-ethylaminophenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(5,6-dichloro-3-iodophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-phenylpiperazine
1-{2(R,S)-[N-(phenethyl)butanamido-4-yl]-2-[3(S)-(2-(cyclopentyl)-3-(propoxycarbonyl)-4-(2-methanesulfonylaminophenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(2,4-dimethylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-methoxycarbonylpiperazine
1-{2(R,S)-[N-(benzyl)pentanamido-5-yl]-2-[3(S)-(2-(cyclopropyl)-3-(isopropoxycarbonyl)-4-(3-nitrophenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(3-methyl-4-isopropylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine naphthalenesulfonate
1-{2(R,S)-[N-(3-trifluoromethylbenzyl)pentanamido-5-yl]-2-[3(S)-(2-(sec-butyl)-3-(butoxycarbonyl)-4-(methoxycarbonyl)imidazolidin-5-on-1-yl)-4(R)-(1-(2-chloro-4-pentylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine oxalate
1-{2(R,S)-[N-(4-carboxamidobenzyl)pentanamido-5-yl]-2-[3(S)-(2-(butyl)-3-(isobutoxycarbonyl)-4-(ethoxycarbonyl)imidazolidin-5-on-1-yl)-4(R)-(1-(2-methyl-3-propoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine maleate
1-{2(R,S)-[N-(3-methoxybenzyl)pentanamido-5-yl]-2-[3(S)-(2-(isopropyl)-3-(tert-butoxycarbonyl)-4-(tert-butoxycarbonyl)imidazolidin-5-on-1-yl)-4(R)-(1-(3,4-dimethoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine citrate
1-{2(R,S)-[N-(phenyl)pentanamido-5-yl]-2-[3(S)-(2-(propyl)-3-(benzyloxycarbonyl)-4-(naphth-1-yl)imidazolidin-5-on-1-yl)-4(R)-(1-(2,3-dibromo-4-isobutoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine phosphate
1-{2(R,S)-[N-phenethyl)pentanamido-5-yl]-2-[3(S)-(2-(ethyl)-3-(2-methylbenzyloxycarbonyl)-4-(naphth-2-yl)imidazolidin-5-on-1-yl)-4(R)-(2-ethylthio-4-methylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine acetate
1-{2(R,S)-[N-(2,4-dichlorophenyl)pentanamido-5-yl]-2-[3(S)-(2-(methyl)-3-(4-isopropylbenzyloxycarbonyl)-4-(3-chloronaphth-1-yl)imidazolidin-5-on-1-yl)-4(R)-(1-(2-chloro-5-isopropyl-3-hexylthiophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine trifluoroacetate
1-{2(R,S)-[N-methyl-N-(benzyl)pentanamido-5-yl]-2-[3(R)-(2-(tert-butyl)-3-(3-methoxybenzyloxycarbonyl)-4-(6-methoxynaphth-2-yl)imidazolidin-5-on-1-yl)-4(S)-(1-(3,4-dimethylthiophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine benzoate
1-{2(R,S)-[N-hydroxy-N-(benzyl)pentanamido-5-yl]-2-[3(R)-(2-(isobutyl)-3-(2-butoxybenzyloxycarbonyl)-4-(5-aminonaphth-1-yl)imidazolidin-5-on-1-yl)-4(S)-(1-(2-nitro-4-methoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine 4-toluenesulfonate
1-{2(R,S)-[N-(2-chlorophenyl)pentanamido-5-yl]-2-[3(S)-(2-(6-nitronaphth-2-yl)-3-(3-chlorobenzyloxycarbonyl)-4-(methyl)imidazolidin-5-on-1-yl)-4(R)-(1-(3-nitro-5-chlorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine trifluoromethanesulfonate
1-{2(R,S)-[N-(3-chloro-4-methoxyphenyl)pentanamido-5-yl]-2-[3(S)-(2-(7-cyanonaphth-2-yl)-3-(3-fluoro-5-methoxybenzyloxycarbonyl)-4-(hydroxymethyl)imidazolidin-5-on-1-yl)-4(R)-(1-(4-nitro-3-methylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine methanesulfonate
1-{2(R,S)-[N-(4-aminobenzyl)pentanamido-5-yl]-2-[3(S)-(2-(4-methylnaphth-2-yl)-3-(3-cyanobenzyloxycarbonyl)-4-(ethyl)imidazolidin-5-on-1-yl)-4(R)-(1-(3-methoxy-4-carboxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine
1-{2(R,S)-[N-(2-hydroxybenzyl)pentanamido-5-yl]-2-[3(S)-(2-(naphth-2-yl)-3-(4-nitrobenzyoxycarbonyl)-4-(2-(methoxycarbonyl)ethyl)imidazolidin-5-on-1-yl)-4(R)-(1-(3-carboxamido-4-isopropylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine hydrochloride
methyl 2(R)-isopropyl-2-[3(S)-(2-(5-methoxynaphth-1-yl)-3-(3-aminobenzyloxycarbonyl)-4-(2-(benzyloxycarbonyl)ethyl)imidazolidin-5-on-1-yl)-4(R)-(1-(fur-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
ethyl 2(R)-isobutyl-2-[3(S)-(2-(3-chloronaphth-1-yl)-3-(2-hydroxybenzyloxycarbonyl)-4-(3-(tert-butoxycarbonyl)propyl)imidazolidin-5-on-1-yl)-4(R)-(1-(pyrrol-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
propyl 2(R)-[1-hydroxy-2,2-dimethylpropyl]-2-[3(S)-(2-(naphth-1-yl)-3-(3-ethylaminobenzyloxycarbonyl)-4-(2-(isobutoxycarbonyl)propyl)imidazolidin-5-on-1-yl)-4(R)-(1-(pyrrol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
isopropyl 2(R)-[(1,1-ethyleneketal)propionyl]-2-[3(S)-(2-(3-nitrophenyl)-3-(4-dimethylaminobenzyloxycarbonyl)-4-(2-(phenoxycarbonyl)ethyl)imidazolidin-5-on-1-yl)-4(R)-(1-(pyridin-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
butyl 2(R)-[(1,1-ethyleneketal)acetyl]-2-[3(S)-(2-(4-methanesulfonylaminophenyl)-3-(benzoyl)-4-(propyl)imidazolidin-5-on-1-yl)-4(R)-(1-(pyridin-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
isobutyl 2(R)-[2,2-dimethylpropionyl]-2-[3(S)-(2-(3-aminophenyl)-3-(3-methylbenzoyl)-4-(3-(thiobenzyl)propyl)imidazolidin-5-on-1-yl)-4(R)-(1-(pyridin-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
sec-butyl 2(R)-[N-benzylcarboxamido]-2-[3(R)-(2-(2-cyanophenyl)-3-(4-tert-butylbenzoyl)-4-(isopropyl)imidazolidin-5-on-1-yl)-4(S)-(1-(thiazol-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
tert-butyl 2(R)-[N-(3-trifluoromethyl)benzylcarboxamido]-2-[3(S)-(2-(4-hydroxyphenyl)-3-(2-isopropoxybenzoyl)-4-(butyl)imidazolidin-5-on-1-yl)-4(R)-(1-(thiazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
pentyl 2(R)-[N-(3-amino)benzylacetamido-2-yl]-2-[3(S)-(2-(2-fluoro-4-methoxyphenyl)-3-(5-fluoro-3-ethoxyphenyl)-4-(3-(thiomethyl) butyl)imidazolidin-5-on-1-yl)-4(R)-(1-(thiazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
hexyl 2(R)-[N-(2-trifluoromethyl)benzylacetamido-2-yl]2-[3(S)-(2-(3-ethoxyphenyl)-3-(4-chlorobenzoyl)-4-(isobutyl)imidazolidin-5-on-1-yl)-4(R)-(1-(oxazol-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
benzyl 2(R)-[N-(2-carboxamido)benzylpropionamido-3-yl]-2-[3(S)-(2-(3-methoxyphenyl)-3-(2,4-dibromobenzoyl)-4-(phenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(oxazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2-chlorobenzyl 2(R)-[N-(4-trifluoromethyl)benzylpropionamido-3-yl]-2-[3(R)-(2-(3isopropxyphenyl)-3-(4-cyanobenzoyl)-4-(2-nitrophenyl)imidazolidin-5-on-1-yl)-4(S)-(1-(oxazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-fluorobenzyl 2(R)-[N-(4-nitro)benzylbutanamido-4-yl]-2-[3(S)-(2-(2-chloro-4-bromophenyl)-3-(3-nitrobenzoyl)-4-(3-ethoxyphenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(isoxazol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-iodobenzyl 2(R)-[N-(3-fluoromethyl)benzylbutanamido-4-yl]-2-[3(S)-(2-(3-iodophenyl)-3-(2-aminobenzoyl)-4-(4-chlorophenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(isoxazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3,4-dibromobenzyl 2(R)-[N-(2-methoxy)benzylpentanamido-5-yl]-2-[3(S)-(2-(4-fluorophenyl)-3-(3-hydroxybenzoyl)-4-(2-ethyl-3-bromophenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(isoxazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2-methylbenzyl 2(R)-[N-(4-methyl)benzylpentanamido-5-yl]-2-[3(S)-(2-(phenyl)-3-(4-dimethylaminobenzoyl)-4-(3-hydroxyphenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(imidazol-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-ethylbenzyl 2(S)-isopropyl-2-[3(S)-(2-(methoxycarbonyl)-3-(3-methanesulfonylaminobenzoyl)-4-(4-cyanophenyl)imidazolidin-5-on-1-yl)-4(R)-(1-(imidazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-isopropylbenzyl 2(S)-isobutyl-2-[3(S)-(3,4-di(acetyloxy)succinimido)-4(R)-(1-(imidazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-bromo-4-tert-butylbenzyl 2(S)-[1-hydroxy-2,2-dimethylpropyl]-2-[3(S)-(3,4-di(isopropionyloxyl)succinimido)-4(R)-(1-(pyrazol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-methoxybenzyl 2(S)-[(1,1-ethylene)ketalpropionyl]-2-[3(R)-(3,4-di(tert-butanoyloxy)succinimido)-4(S)-(1-(pyrazol-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-ethoxybenzyl 2(S)-[1,1-ethyleneketal)acetyl-2-[3(S)-4(R)-(1-(pyrazol-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2-isopropylbenzyl 2(S)-(2,2-dimethylpropionyl]-2-[3(S)-(3, 4-di(pentanoyloxy)succinimido)-4(R)-(1-(pyrimidin-2-yl)ethylen-2-yl)azetidin-2-on-1-yl)acetate
3-tert-butyl-4-chlorobenzyl 2(S)-[N-benzylcarboxamido]-2-[3(R)-(3,4-di(benzoyloxy)succinimido)-4(S)-(1-(pyrimidin-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-nitrobenzyl 2(S)-[N-(3-trifluoromethyl)benzylcarboxamido]-2-(3(S)-(3,4-di(2-methylbenzoyloxy)succinimido)-4(R)-(1-(pyrimidin-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-aminobenzyl 2(S)-[N-(3-methylamino)benzylacetamido-2-yl]-2-[3(S)-(3,4-di(3-ethylbenzoyloxy)succinimido)-4(R)-(1-(pyrimidin-6-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-methyl-3,5-dichlorobenzyl 2(S)-[N-(3-dimethylamino)benzylacetamido-2-yl]-2-[3(S)-(3,4-di(4-isobutylbenzoyloxy)succinimido)-4(R)-(1-(thiadiazol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2-cyanobenzyl 2(S)-[N-(2-trifluoromethyl)benzylpropionamido-3-yl]-2-[3(S)-(3,4-di(3,5-dimethylbenzoyloxy)succinimido)-4(R)-(1-(oxadiazol-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
4-hydroxybenzyl 2(S)-[N-(3-carboxamido)benzylpropionamido-3-yl]-2-[3(S)-(3,4-di(2-methoxybenzoyloxy) succinimido)-4(R)-(1-(quinolin-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
3-carboxamidobenzyl 2(S)-[N-(4-trifluoromethyl)benzylbutanamido-4-yl]-2-[3(S)-(3,4-di(3-tert-butoxybenzoyloxy)succinimido)-4(R)-(1-(quinolin-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
2,4,5-trichlorobenzyl 2(S)-[N-(2-nitro)benzylbutanamido-4-yl]-2-[3(S)-(3,4-di(3,4-diethoxybenzoyloxy)succinimido)-4(R)-(1-(quinolin-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetate
N-[phenyl]-2(S)-[N-(2-fluoro-3-methyl)benzylbutanamido-4-yl]-2-[3(S)-(3,4-di(4-fluorobenzoyloxy)succinimido)-4(R)-(1-(quinolin-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-trifluoromethylbenzyl]-2(S)-[N-(4-methoxy)benzylpentanamido-5-yl]-2-[3(S)-(3,4-di(2-chlorobenzoyloxy)succinimido)-4(R)-(1-(quinolin-6-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[cyclopropyl]-2(S)-[N-(4-isopropyl)benzylpentanamido-5-yl]-2-[3(S)-(3,4-di(3,4-dibenzoyloxy)succinimido)-4(R)-(1-(quinolin-7-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[cyclobutylethyl]-2(R,S)-isopropyl-2-[3(S)-(3,4-di(3-methoxy-4-chlorobenzoyloxy)succinimido)-4(R)-(1-(quinolin-8-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[cyclopentyl]-2(R,S)-isobutyl-2-[3(S)-(3,4-di(4-cyanobenzoyloxy)succinimido)-4(R)-(1-(isoquinolin-1-yl)-ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[phenethyl]-2(R,S)-[1-hydroxy-2,2-dimethylpropyl]-2-[3(S)-(3,4-di(3-nitrobenzoyloxy)succinimido)-4(R)-(1-(isoquinolin-3-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[phenpropyl]-2(R,S)-[(1,1-ethyleneketal)propionyl]-2-[3(S)-(3,4-di(2-aminobenzoyloxy)succinimido)-4(R)-(1-(isoquinolin-4-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-trifluoromethylbenzyl]-2(R,S)-[(1,1-ethyleneketal)acetyl]-2-[3(S)-(3,4-di(4-methoxycarbonylbenzoyloxy)succinimido)-4(R)-(1-(isoquinolin-5-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[4-chlorobenzyl]-2(R,S)-[2,2-dimethylpropionyl]-2-[3(S)-(3,4-di(benzoyloxy)succinimido)-4(R)-(1-(isoquinolin-6-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[2-bromobenzyl]-2(R,S)-[N-benzylcarboxamido]-2-[3(S)-(3,4-di(diphenylmethoxy)succinimido)-4(R)-(1-(isoquinolin-7-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-fluorobenzyl]-2(R,S)-[N-(3-trifluoromethyl)benzylcarboxamido]-2-[3(S)-(3,4-di(triphenylmethoxy)succinimido)-4(R)-(1-(isoquinolin-8-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[2-methylbenzyl]-2(R,S)-[N-phenylcarboxamido]-2-[3(S)-(3-acetyloxysuccinimido)-4(R)-(1-(naphth-1-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-chloro-4-isopropylbenzyl]-2(R,S)-[N-(2-chlorophenyl)carboxamido]-2-[3(S)-(3-isopropionyloxysuccinimido)-4(R)-(1-(naphth-2-yl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[2,4-dimethoxybenzyl]-2(R,S)-[N-(4-methylphenyl)carboxamido]-2-[3(S)-(3-tert-butanoyloxysuccinimido)-4(R)-(1-(2-fluorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[3-isopropoxybenzyl]-2(R,S)-[N-(3-isopropylphenyl)carboxamido]-2-[3(S)-(3-pentanoyloxysuccinimido)-4(R)-(1-(3-chlorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[4-sulfonamidobenzyl]-2(R,S)-[N-(4-trifluoromethylphenyl)carboxamido]-2-[3(S)-(3-(2-methylbenzoyloxy)succinimido)-4(R)-(1-(4-bromophenyl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
N-[quinuclidin-2-yl]-2(R,S)-[N-(4-methylphenyl)carboxamido]-2-[3(S)-(3-ethylbenzoyloxy)-4(R)-(1-(3-iodophenyl)ethylen-2-yl)azetidin-2-on-1-yl]acetamide
1-{2(R,S)-[N-(3-trifluoromethylbenzyl]acetamido-2-yl]-2-[3(S)-(3-(4-isobutylbenzoyloxy)succinimido)-4(R)-(1-(2-methylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-1,2,3,4-tetrahydronaphthalene
1-{2(R,S)-[N-(benzyl)acetamido-2-yl]-2-[3(S)-(3-(3,5-dimethylbenzoyloxy)succinimido)-4(R)-(1-(3-isopropylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-hydroxypiperidine
1-{2(R,S)-[N-(4-chlorophenyl)acetamido-2-yl]-2-[3(S)-(3-(2-methoxybenzoyloxy)succinimido)-4(R)-(1-(4-pentylphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}4-(piperidin-1-yl)piperidine
1-{2(R,S)-[N-(2-cyanophenyl)acetamido-2-yl]-2-[3(R)-(3-(3-tert-butoxybenzoyloxysuccinimido)-4(S)-(1-(2-propoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-benzylpiperidine
1-{2(R,S)-[N-(phenylethyl)acetamido-2-yl]-2-[3(S)-(3-(3,4-diethoxybenzoyloxy)succinimido)-4(R)-(1-(3-methoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-((piperidin-1-yl)methyl)piperidine
1-{2(R,S)-[N-(benzyl)propionamido-3-yl]-2-[3(S)-(3-(4-fluorobenzoyloxy)succinimido)-4(R)-(1-(4-isobutoxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(2-(piperidin-1-yl)ethyl)piperidine
1-{2(R,S)-[N-(3-trifluoromethylbenzyl)propionamido-3-yl]-2-(3(R)-(3-(2-chlorobenzoyloxy)succinimido)-4(S)-(1-(2-ethylthiophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(3-(piperidin-1-yl)propyl)piperidine
1-{2(R,S)-[N-(3-fluorophenyl)propionamido-3-yl]-2-[3(S)-(3-(3, 4-dibromobenzoyloxy)succinimido)-4(R)-(1-(3-hexylthiophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-(4-(piperidin-1-yl)butyl)piperidine
1-{2(R,S)-[N-(3-aminophenyl)propionamido-3-yl]-2-[3(S)-(3-(3-methoxy-4-iodobenzoyloxy)succinimido)-4(R)-(1-(4-methylthiophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-2,4-dimethylpiperidine
1-{2(R,S)-[N-(benzyl)propionamido-3-yl]-2-[3(S)-(3-(4-cyanobenzoyloxy)succinimido)-4(R)-(1-(2-nitrophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-3,5-dimethylpiperidine
1-{2(R,S)-[N-(3-methylbenzyl)propionamido-3-yl]-2-[3(S)-(3-(3-nitrobenzoyloxy)succinimido)-4(R)-(1-(3-nitrophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-methylpiperidine
1-{2(R,S)-[N-(4-isopropoxybenzyl)propionamido-3-yl]-2-[3(S)-(3-(2-aminobenzoyloxy)succinimido)-4(R)-(1-(4-nitrophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-isopropylpiperazine
1-{2(R,S)-[N-(3-iodobenzyl)propionamido-3-yl]-2-[3(S)-(3-(4-methoxycarbonylbenzoyloxy)succinimido)-4(R)-(1-(2-carboxyphenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-phenethylpiperazine
1-{2(R,S)-[N-(phenethyl)propionamido-3-yl]-2-[3(S)-(3-(benzyl)oxysuccinimido)-4(R)-(1-(3-carboxamidophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-cyclohexylpiperazine
1-{2(R,S)-[N-(benzyl)butanamido-4-yl]-2-[3(S)-(3-(diphenylmethoxy)succinimido)-4(R)-(1-(2,3-difluorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-cyclopropylpiperazine
1-{2(R,S)-[N-(3-trifluoromethylbenzyl)butanamido-4-yl]-2-[3(S)-(3-(triphenylmethoxy)succinimido)-4(R)-(1-(3,5-dichlorophenyl)ethylen-2-yl)azetidin-2-on-1-yl]}-4-benzylpiperazine
The 2-(azetidinon-1-yl)acetic acid esters and amides of Formula I are prepared by methods well known in the art. The 2-(azetidinon-1-yl)acetic acid esters are obtainable by the 2+2 cycloaddition of an appropriately substituted acetic acid derivative (i), and an imine ester (ii) as described in Synthetic Scheme I. Z is halo, acyloxy or benzoyloxy, and R1, R2, R3, R4, and R9 are as previously described. While the chemistry described in Synthetic Scheme I is applicable to imines (ii) bearing ester, thioester or amide moieties, only the esters are illustrated.
Synthetic Scheme I 
The preparation of the appropriate imines (ii) and most of the required acetyl halides or anhydrides (i), as well as the cycloaddition procedure, are generally described in U.S. Pat. Nos. 4,665,171 and 4,751,299, hereby incorporated by reference.
Those compounds of the invention requiring R3 to be 4 substituted oxazolidin-2-on-3-yl are prepared from the corresponding (4-substituted oxazolidin-2-on-3-yl)acetyl halide or anhydride. The acid halide or anhydride is available from an appropriately substituted glycine. The glycine is first converted to the carbamate and then reduced to provide the corresponding alcohol. The alcohol is then cyclized to the 4-substituted oxazolidin-2-one, which is subsequently N-alkylated with a haloacetic acid ester, the ester deesterified, and the acid converted to the acetyl halide or anhydride (i).
Those compounds of the invention requiring R3 to be 2,5-disubstituted oxazolidin-4-on-3-yl or 1,2,5-trisubstituted imidazolidin-4-on-3-yl are prepared from the corresponding (2,5-disubstituted oxazolidin-4-on-3-yl)- or (1,2,5-trisubstituted imidazolidin-4-on-3-yl)acetyl chlorides or anhydrides respectively. The chemistry to prepare these reagents is described in U.S. Pat. No. 4,772,694, hereby incorporated by reference. Briefly, the required oxazolidinone or imidazolidinone is obtained with an xcex1-hydroxyacid or an xcex1-aminoacid, respectively. The imidazolones are prepared by converting the xcex1-aminoacid, (R12)xe2x80x94CH(NH2)CO2H, to an amino-protected amide and then condensing the amide with an aldehyde, (R11)xe2x80x94CHO, in the presence of an acid to form the 3-protected imidazolidin-4-one. The 1-position may be functionalized with an appropriate reagent to introduce R13 and the 3-position deprotected. The imidazolidin-4-one ring is then alkylated with a haloacetic acid ester, the ester deesterified, and the resulting acetic acid converted to the desired acid halide or anhydride (i). The required oxazolidinones are prepared in an analogous manner from the corresponding xcex1-hydroxyacid, (R12)xe2x80x94CH(OH)CO2H.
Those compounds of the invention requiring R3 to be succinimido are prepared from the corresponding 2-(succinimido)acetyl halide or anhydride. The chemistry to prepare these reagents is described in U.S. Pat. No. 4,734,498, hereby incorporated by reference. Briefly, these reagents are obtained from tartaric acid or, when one of R14 and R15 is hydrogen, from malic acid. Tartaric acid is acylated or O-alkylated, the corresponding diacyl or di-O-alkyl tartaric acid treated with an acid anhydride to form the succinic anhydride, and reaction of this succinic anhydride with an ester of glycine to form first the noncyclic half amide ester which is then cyclized to the 3,4-disubstituted succinimidoacetic acid ester. The ester group is deesterified and the resulting acid converted to the corresponding acid halide or anhydride (i). The mono-substituted succinimidoacetyl halide or anhydride is obtained with malic acid via succinic anhydride formation followed by succinimide formation as described above.
As discussed supra, the compounds prepared as described in Synthetic Scheme I may be pure diastereomers, mixtures of diastereomers, or racemates. The actual stereochemical composition of the compound will be dictated by the specific reaction conditions, combination of substituents, and stereochemistry of the reactants employed in Synthetic Scheme I. The skilled artisan will appreciate that diasteromeric mixtures may be separated by chromatography or fractional crystallization to provide single diastereomers if desired.
The bases to be used in Synthetic Scheme I include, among others, aliphatic tertiary amines, such as trimethylamine and triethylamine, cyclic tertiary amines, such as N-methylpiperidine and N-methylmorpholine, aromatic amines, such as pyridine and lutidine, and other organic bases such as 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
The solvents useful for reactions described in Synthetic Scheme I include, among others, dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, acetonitrile, dimethyl sulfoxide and N,N-dimethylformamide.
Compounds of Formula I where R1 and R2 are hydrogen, while useful vasopressin V1a agents in their own right, are also useful synthetic intermediates for the preparation of compounds where R1 is C1-C5 acyl, C3-C6 cycloalkylcarbonyl, xe2x80x94(C1-C4 alkylene)C(O)NR5X, benzoyl, phenoxyacetyl, phenylacetyl where the phenyl is optionally substituted with halo, C1-C4 alkyl, C1-C4 alkoxy, or trifluoromethyl, or xcex1-hydroxy-xcex1-benzoylbenzyl, as well as compounds where R1 is hydroxy substituted C1-C5 alkyl and R2 is hydrogen, or compounds where both R1 and R2 are hydroxy substituted C1-C5 alkyl. The preparation of these compounds is described in Synthetic Scheme II. 
R2xe2x80x2 represents hydrogen; C1-C4 alkyl; C3-C6 cycloalkyl; phenyl; phenoxymethyl; or benzyl where the phenyl group is optionally substituted with halo, C1-C4 alkyl, C1-C4 alkoxy or trifluoromethyl; R2xe2x80x3 represents C1-C5 alkyl; Z represents halo; C1-C4 alkoxy; or R2xe2x80x2C(O)xe2x80x94; and R3, R4, R5, Q, X, and Xxe2x80x2 are as previously defined. The reaction described in Synthetic Scheme II creates a chiral center at the carbon bearing R1 and R2. The skilled artisan will appreciate that the racemic mixture may be separated into separate stereoisomers by fractional crystallization or chromatography if desired.
A solution of the 2-(3,4-disubstituted azetidin-2-on-1-yl)acetic acid derivative in an appropriate solvent, such as tetrahydrofuran, dioxane or diethyl ether, is treated with a non-nucleophilic base to generate the anion (iii). Suitable bases for this transformation include lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidinamide, or lithium bis(trimethylsilyl)amide. The anion is then quenched with an appropriate electrophile to provide the desired compounds. Electrophiles of formula R2xe2x80x2C(O)Z, representing esters, acid halides and anhydrides, provide the corresponding carbonyl containing derivatives. Electrophiles of formula R2xe2x80x3C(O)H provide the corresponding alcohols. Electrophiles of formula halo-(CH2)1-4xe2x80x94C(O)NR5Xxe2x80x2 provide the corresponding (C1-C4 alkylene)carboxamides. The skilled artisan will appreciate that reaction of the anion (iii) with benzil provides compounds of the invention where R2 is xcex1-hydroxy-xcex1-benzoylbenzyl. The skilled artisan furthermore will appreciate that treatment of alcohol (iv) with a second equivalent of base and additional electrophile of formula R2xe2x80x3C(O)H provides the disubstituted compounds of the invention (v).
Compounds of Formula I which are 2-(3,4-disubstituted azetidin-2-on-1-yl)acetate esters, while useful vasopressin V1a agents in their own right, may also be converted to the corresponding carboxylic acid to provide intermediates useful for the preparation of other compounds of the invention as illustrated in Synthetic Scheme III. R1, R2, R3, R4, R5, R9, and Xxe2x80x2 are as previously defined. 
The requisite carboxylic acid may be prepared from the corresponding ester by saponification under standard conditions by treatment with hydroxide followed by protonation of the resultant carboxylate anion. Where R9 is tert-butyl, the ester may be dealkylated by treatment with trifluoroacetic acid. Where R9 is benzyl, the ester may be dealkylated either by subjection to mild hydrogenolysis conditions, or by reaction with elemental sodium or lithium in liquid ammonia. Finally, where R9 is 2-(trimethylsilyl)ethyl, the ester is deprotected by treatment with a source of fluoride ion, such as tetrabutylammonium fluoride. The choice of conditions is dependent upon the nature of the R9 moiety and computability of other functionality in the molecule to the reaction conditions.
The carboxylic acid is converted to the corresponding amide under standard conditions well recognized in the art. The acid may be first converted to the corresponding acid halide, preferably the chloride or fluoride, followed by treatment with an appropriate primary or secondary amine to provide the corresponding amide. Alternatively, the acid may be converted under standard conditions to a mixed anhydride. This is typically accomplished by first treating the. carboxylic acid with an amine, such as triethylamine, to provide the corresponding carboxylate anion. This carboxylate is then reacted with a suitable haloformate, for example benzyl chloroformate, ethyl chloroformate or isobutylchloroformate, to provide the corresponding mixed anhydride. This anhydride may then be treated with an appropriate primary or secondary amine to provide the desired amide. Finally, the carboxylic acid may be treated with a typical peptide coupling reagent such as N,Nxe2x80x2-carbonyldiimidazole (CDI), N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), followed by the appropriate amine of formula HNR5X. A polymer supported form of EDC has been described (Tetrahedron Letters, 34(48), 7685 (1993)) and is very useful for the preparation of the compounds of the present invention. The skilled artisan will appreciate that substituting an appropriate amine with an appropriate alcohol will provide the esters of the invention. The skilled artisan will furthermore appreciate that, for those compounds where the R1 moiety is xe2x80x94C(O)NR5Xxe2x80x2 or xe2x80x94(C1-C4 alkylene)C(O)NR5Xxe2x80x2, the variables R5 and X of the amine, HNR5Xxe2x80x2, used for the preparation of the amide described supra, may be the same or different as those selected for the moiety R1.
Compounds of Formula I where R4 is 2-arylethen-1-yl may be converted into the corresponding arylethyl derivatives by subjecting the substrate to standard hydrogenation conditions as described in Synthetic Scheme IV. R1, R2, R3, Q, and X are as previously defined. 
The hydrogenation of the double bond proceeds readily over a precious metal catalyst, such as palladium on carbon. The hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of 20-80 p.s.i., preferably from 50-60 p.s.i., at 0-60xc2x0 C., preferably at ambient temperature to 40xc2x0 C, for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate.
Compounds of Formula I where R3 is phthalimido are conveniently treated with hydrazine or a hydrazine derivative, for example methylhydrazine, to prepare the corresponding 2-(3-amino-4-substituted azetidin-2-on-1-yl)acetic acid derivative. This compound may then be treated with an appropriate isocyanate to prepare the corresponding ureas as illustrated in Synthetic Scheme V. R1, R2, R4, R6, Q, and X are as previously defined. 
The ureas are prepared by treating a solution of the appropriate amine in a suitable solvent, such as chloroform or dichloromethane, with an appropriate isocyanate. If necessary, an excess of the isocyanate is employed to ensure complete reaction of the starting amine. The reactions are performed at about ambient to about 45xc2x0 C., for from about three hours to about three days. Typically, the product may be isolated by washing the reaction with water and concentrating the remaining organics under reduced pressure. When an excess of isocyanate has been used, however, a polymer bound primary or secondary amine, such as an aminomethylated polystyrene, maybe conveniently added to react with the excess reagent. Isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
The skilled artisan will appreciate that, in many cases, the order of the steps described above is not critical. For example, an appropriate xcex1-amino acid may be suitably substituted by chemistry generally described in Synthetic Schemes II and III prior to subjecting it to the 2+2 cycloaddition described in Synthetic Scheme I to provide a compound of the invention.